Vascular endothelial growth factor (VEGF) signaling controls blood vessel development and plays a central role in the vascularization of malignant tumors. The most important receptors for VEGF are part of the receptor tyrosine kinase (RTK) family. Receptor dimerization is an important step in the activation of RTK receptors. Concentration or clustering of receptors in islands representing a small fraction of the total membrane surface is another feature of RTK signaling, believed to increase its efficiency. The role of these phenomena in signaling and the origin and mechanism of receptor clustering are not well understood and are subject to intense experimental and theoretical efforts. This project on VEGF complements ongoing work focused on other RTK receptor families such as EGF. We propose to investigate the role of spatial structure in the kinetics of VEGF signaling and infer the spatial distribution of VEGF receptors in the cell membrane and its dependence on the presence of ligand, in a specific cell system. Experimentally we plan to use advanced imaging methods which allow the visualization of individual receptors and infer their spatial distribution and mobility, as well as flow cytometry to investigate signaling in individual cells. Based on data collected on the same cellular system, we will build a spatial Monte-Carlo model of the molecular processes involved in signaling, including two-dimensional movement in the cell membrane. We will use this model to investigate the interplay between spatial features of the cell membrane, receptor clustering, and signal transduction. Finally, we seek to encapsulate the emerging understanding of spatial aspects of VEGF binding in lower dimensional representations, with the goal of defining a realistic, whole-cell model of the first step in VEGF signaling, which can be incorporated in models on the scale of tissues.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Mentored Quantitative Research Career Development Award (K25)
Project #
5K25CA131558-05
Application #
8304298
Study Section
Subcommittee G - Education (NCI)
Program Officer
Jakowlew, Sonia B
Project Start
2008-09-19
Project End
2014-02-28
Budget Start
2012-09-01
Budget End
2014-02-28
Support Year
5
Fiscal Year
2012
Total Cost
$125,402
Indirect Cost
$7,748
Name
West Virginia University
Department
Biostatistics & Other Math Sci
Type
Schools of Arts and Sciences
DUNS #
191510239
City
Morgantown
State
WV
Country
United States
Zip Code
26506
Pryor, Meghan McCabe; Low-Nam, Shalini T; Halasz, Adam M et al. (2013) Dynamic transition states of ErbB1 phosphorylation predicted by spatial stochastic modeling. Biophys J 105:1533-43
Radhakrishnan, Krishnan; Halász, Adám; Vlachos, Dion et al. (2010) Quantitative understanding of cell signaling: the importance of membrane organization. Curr Opin Biotechnol 21:677-82